A number of synthetic modifications of the vasopressin and oxytocin structures have been reported to give antagonistic activities. Such structures contain units which are derived from .beta.-mercaptopropionic acids, for example, desamino-penicillamine or .beta.-mercaptopropionic acid, substituted for the cysteine unit at position 1 of the structure of the natural product: J. Loweridge et al., J. Med Chem. 22 565 (1979); M. Manning et al., J. Med. Chem. 20 1228 (1977); K. Bankowski et al., J. Med. Chem. 21 350 (1978); H. Schulz et al., J. Med. Chem. 9 647 (1966). Ferring, A.B., European Patent No. 112,809-A discloses that certain Mpr.sub.1 oxytocin derivatives have oxytocin antagonist activity.
Later studies by M. Manning et al., J. Med. Chem. 25 408 (1982) and Peptides: Chemistry, Structure and Biology (Ann Arbor Sciences) 737 (1975), demonstrated that no clearly consistent pattern of increasing or decreasing antagonist potency has emerged from research in this area but, in most of the series studied, the .beta.,.beta.-diethyl and .beta.,.beta.-cyclopentamethylene propionic acid units at position 1 were much more active than were the lower homologues, see column 1 on page 411 of the first Manning reference.
Ser. No. 535,000, a U.S. application which was earlier filed and is commonly assigned, but is now abandoned in favor of pending Ser. No. 645,127, discloses the preparation and V.sub.2 -antagonistic activity of certain vasopressin-like compounds having a 1-(.beta.-mercapto-.beta.,.beta.-cycloalkylene)-propionic acid at position 1 and a diaminoalkyl group at position 7 or 8.
In the description herein and in the claims, the nomenclature common in the art of peptide and, more specifically, vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L or naturally occuring form. The thio members of the .beta.-mercaptopropionic acid (1) and cysteine (6) units are added for clarity in certain structural formulas.
Exemplary of the peptide art designations used herein are the following: dPen, .beta.-mercapto-.beta.,.beta.-dimethylpropionic acid; Put, putrescine; Cad, cadaverine; Mpr, .beta.-mercaptopropionic acid; Trp, tryptophan; Thr, threonine; OXT, oxytocin; Abu, .alpha.-aminobutyric acid; Chg, cyclohexylglycine; Cha, cyclohexylalanine, Pba, .alpha.-aminophenylbutyric acid; Gln, glutamine; Gly, glycine; Tyr, tyrosine; Phe, phenylalanine; Val, valine; Ile, isoleucine; Nle, norleucine; Leu, leucine; Ala, alanine; Lys, lysine; Asn, asparagine; Tos, tosylate; Sar, sarcosine; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid, DCC, dicyclohexylcarbodiimide; HBT, 1-hydroxybenzotriazole; ACM, acetamidomethyl; Mpa, generic .beta.-mercaptopropionic acids of the present invention.